RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury

Xinzhou Zhu,Sven Wellmann,Raphael Guzman,Catherine Bregere,Tessa Goerne,Andrea Zelmer,Josef P Kapfhammer,Jingyi Yan

doi:10.1038/s41467-019-11870-x

Abstract

Hypoxic ischemia (HI) is an acute brain threat across all age groups. Therapeutic hypothermia ameliorates resulting injury in neonates but its side effects prevent routine use in adults. Hypothermia up-regulates a small protein subset that includes RNA-binding motif protein 3 (RBM3), which is neuroprotective under stressful conditions. Here we show how RBM3 stimulates neuronal differentiation and inhibits HI-induced apoptosis in the two areas of persistent adult neurogenesis, the subventricular zone (SVZ) and the subgranular zone (SGZ), while promoting neural stem/progenitor cell (NSPC) proliferation after HI injury only in the SGZ. RBM3 interacts with IGF2 mRNA binding protein 2 (IMP2), elevates its expression and thereby stimulates IGF2 release in SGZ but not SVZ-NSPCs. In summary, we describe niche-dependent regulation of neurogenesis after adult HI injury via the novel RBM3-IMP2-IGF2 signaling pathway.

Highlights

Hypoxic ischemia (HI) is an acute brain threat across all age groups
In studying its role in adult neurogenesis we found no difference in brain weight between adult RNA-binding motif protein 3 (RBM3) KO and wild-type (WT) mice raised under normal conditions (Supplementary Fig. 1a)
The present study confirmed its expression in sex determining region Y-box 2 (Sox2)+ neural stem/progenitor cell (NSPC) and Dcx + neuroblasts in both the subventricular zone (SVZ) and subgranular zone (SGZ) in vivo (Supplementary Fig. 1c, d)

Summary

Introduction

Hypoxic ischemia (HI) is an acute brain threat across all age groups. Therapeutic hypothermia ameliorates resulting injury in neonates but its side effects prevent routine use in adults. The total number and density of proliferating (BrdU+ Sox2+) NSPCs in KO mice was similar to that in WT mice in both the SVZ and SGZ niches (Supplementary Fig. 1e, f). After 7 days recovery from HI, total BrdU+ cell density in the SVZ and DG were both increased in the ipsilateral side of WT and KO mice compared to contralateral side, but no difference was observed between WT and KO mice (Supplementary Fig. 2c, d).

Results

Conclusion